Multidrug resistance (MDR), defined as the resistance of tumors to a wide spectrum of drugs, is a major limitation of cancer chemotherapy. MDR in at least some cells is due to the overexpression of the P-glycoprotein (PGP)/MDR gene. PGP is a member of a family of adenosine triphosphate (ATP)- dependent transporters and has been shown to cause the efflux of a large variety of compounds from the cell. The gene family is known as the ATP-binding cassette (ABC) family, and its members transport multiple diverse compounds across biological membranes. Human ABC genes are involved in a number of diseases including cystic fibrosis, adrenoleukodystrophy, and familial persistent hyperinsulinemic hypoglycemia. Recently a gene, termed MRP, was identified as being overexpressed in a multidrug-resistant lung tumor cell, and appears to be a transporter for drug-glutathione conjugates. MRP is also a member of the ABC family of transporters. To identify new genes involved in the attainment of multidrug resistance we have identified and characterized new MDR and MRP-related genes from several different tissues. In addition, we have cloned a Caenorhabditis elegans homolog of the human MRP gene and disrupted this gene to develop a model system to study MRP function. The objective of this project is to explore the role of these genes in normal and malignant cells, and to develop model systems to study their function.